Activation imposes on T cells a high energetic demand that is necessary to sustain effector functions and cell proliferation. If those requirements are not met cells fail to activate and can enter instead a state of unresponsiveness. We have recently shown that activation of macroautophagy, a catabolic process that directs the degradation of different cytosolic components in the lysosomes, in CD4+ T cells is required for the generation of the levels of ATP that guarantee proper activation. Our most recent data supports that if macroautophagy activity is blocked following TCR+CD28 engagement, CD4+ T cells not only fail to proliferate and secrete cytokines but they also become unresponsive, unable to mount productive responses to subsequent stimulations. This places macroautophagy as a key regulator of the establishment of T cell tolerance through the regulation of the cell's energy metabolism. In this proposal we intend to elucidate the molecular mechanisms that regulate the induction macroautophagy in activated T cells and determine how this form of autophagy modulates T cell responses and controls T cell fate. The proposed studies should not only identify a new process involved in the establishment of T cell tolerance but would also identify new molecular targets that can be used to regulate immune tolerance through the modulation of macroautophagy.